Phencyclidine derivatives, preparation method and pharmaceutical compositions containing same

ABSTRACT

The invention concerns novel phenylcyclidine derivatives with selective affinity for low affinity receptors, methods for preparing them, pharmaceutical compositions containing them and their use as protective agents for central or peripheral nervous system cells against acute or chronic degeneration, or as an anticonvulsant.

This application is a 371 of PCT/FR98/01108 filed Jun. 2, 1998.

The [N-(1-phenylcyclohexyl)piperidine (or PCP), developed as ananesthesic agent then withdrawn due to its very significant psychotopiceffect, is today no more than a pharmalogical tool, interesting at leastthrough its derivatives or analogues. One of the derivatives,N-(1-(2-thienyl)cyclohexyl)piperidine (or TCP), is, in its tritiatedform, a ligand often used as a label for the PCP receptor. In vitro andin vivo studies of the [³H]TCP bond to the PCP receptor has revealed theexistence of a second type of bond corresponding to the said PCP sitesof low affinity in comparison to the first said sites of high affinity(Brain Res., 378, 133-141(1986)).

The present invention relates to novel derivatives of phencyclidineswith selective affinity for low affinity receptors, processes for theirpreparation, pharmaceutical compositions containing them and their useas protective agents for central or peripheral nervous system cellsagainst acute or chronic degeneration or as an anticonvulsant.

Therefore the subject of the invention is the compounds of formula Icharacterized in that they correspond either to formula I_(A)

in which

Ar represents a carboxcylic or heterocyclic aryl radical, monocyclicwith 5 or 6 members or constituted by condensed rings, and optionallysubstituted by one or more identical or different radicals chosen fromhalogen atoms, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,haloalkyl, hydroxyalkyl radicals, having at most 6 carbon atoms; freeesterified or salified carboxy; cyano; nitro; amino optionallysubstituted by one or two identical or different alkyl radicalscontaining at most 6 carbon atoms;

R₁ and R₂ identical or different represent a hydrogen atom or an alkylradical having at most 6 carbon atoms optionally substituted by one ormore identical or different radicals chosen from the hydroxyl, freeesterified or salified carboxy, cyano, nitro radicals, or R₁ and R₂ formwith the nitrogen atom to which they are linked a

 radical in which n represents an integer from 0 to 2 and R₃ and R′₃identical or different represent a hydrogen atom, a halogen atom or ahydroxyl, free esterified or salified carboxy, cyano, nitro, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl radicalhaving at most 6 carbon atoms;

R₄ has the same meaning as R₃ or R′₃;

X, Y and Z are such that at least one represents a sulphur or oxygenatom and the others represent a methylene radical,

with the exception of the compounds in which R₃, R′₃ and R4 eachrepresents a hydrogen atom and

1) R₁ and R₂ form with the nitrogen atom to which they are linked apyrrolidine radical, Ar represents a phenyl or 2-thienyl radical and oneof X, Y and Z represents an oxygen atom,

2) R₁ and R₂ form with the nitrogen atom to which they are linked apiperidine radical, Ar represents a phenyl, thienyl and benzothienylradical, Y represents a sulphur atom and X and Z each represent amethylene radical,

3) R₁ and R₂ form with the nitrogen atom to which they are linked apiperidine radical, Ar represents a phenyl, methoxyphenyl, benzothienylor 2-thienyl radical, Y represents an oxygen atom and X and Z eachrepresent a methylene radical,

4) R₁ and R₂ form with the nitrogen atom to which they are linked apiperidine radical, Ar represents a phenyl, methoxyphenyl or 2-thienylradical, one of X or Z represents an oxygen atom, the other represents amethylene radical and Y represents a methylene radical,

5) R₁ and R₂ form with the nitrogen atom to which they are linked apiperidine radical, Ar represents a phenyl or 2-thienyl radical, one ofX or Z represents a sulphur atom, the other represents a methyleneradical and Y represents a methylene radical,

6) R₁ and R₂ form with the nitrogen atom to which they are linked apyrrolidine radical, Ar represents a 2-thienyl radical, one of X or Zrepresents a sulphur atom, the other represents a methylene radical andY represents a methylene radical,

7) R₁ and R₂ form with the nitrogen atom to which they are linked anethylamino or pyrrolidine radical, Ar represents a phenyl radical, Yrepresents a sulphur atom and X and Z each represent a methyleneradical,

or one of the following formulae:

—N-[1-(2-thienyl)-cyclohexan- 1-yl]-3-hydroxymethyl-piperidine,

—N-[1-(2-thienyl)-cyclohexan- 1-yl]-4-hydroxy-3-methyl piperidine,

—N-[1-(2-benzothiophenyl)-cyclohexan-1-yl]-4-hydroxy-3-methylpiperidine,

—N-ethyl-1-(2-thienyl)-cyclohexylamine or

—N-[1-(2-furyl)-cyclohexan-1-yl] piperidine,

said compounds of formula I being in all possible racemic, enantiomericand diastereoisomeric isomer forms as well as the addition salts withmineral and organic acids or with mineral and organic bases of saidcompounds of formula I.

A more particular subject of the invention is the compounds of generalformula IA as defined below in which

Ar represents an heterocyclic aryl radical, monocyclic with 5 members orconstituted by two condensed rings, and optionally substituted by one ormore identical or different alkyl or alkenyl radicals;

R₁ and R₂, identical or different, represent a hydrogen atom or an alkylradical having at most 6 carbon atoms or R₁ and R₂ form together with anitrogen atom to which they are linked a

radical in which n is equal to 1 and R₃ and R′₃, identical or different,represent a hydrogen atom or a hydroxyl. aklyl or hydroxyalkyl radicalhaving at most 6 carbon atoms.

In the definitions indicated above, the expression halogen represents afluorine, chlorine, bromine or iodine atom.

The expression alkyl having at most 6 carbon atoms represents a linearor branched alkyl radical such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl orisohexyl radical.

Among the alkenyl radicals. The linear or branched alkyl radicals suchas vinyl, allyl, 1-propenyl, butenyl, pentynyl or hexynyl radicals canbe mentioned.

Among the alkynyl radicals, the ethynyl, propargyl, butynyl, pentynyl orhexynyl radicals can be mentioned. The linear or branched alkoxy radicalpreferably designates the radicals in which the alkyl radical is asdefined above. The methoxy, ethoxy, propoxy, isopropyloxy or butoxyradicals are preferred.

The alkylthio radical preferably designates the radicals in which thealkyl radical is as defined above such as for example methylthio orethylthio.

The haloalkyl radical preferably designates the radicals in which thealkyl radical is as defined above and is substituted by one or morehalogen atoms as defined above such as, for example, bromoethyl,trifluoromethyl, trifluoroethyl or also pentafluoroethyl.

The hydroxyalkyl radical preferably designates the radicals in which thealkyl radical is as defined above such as for example hvdroxymethyl orhydroxyethyl.

The aryl radical can be carbocyclic or heterocyclic. The heterocyclicaryl radical can contain one or more identical or different heteroatomschosen from oxygen, nitrogen and sulphur atoms. As an example of acarbocyclic or heterocyclic aryl radical, the phenyl. naphthyl, thienyl,furyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, diazolyl, oxadiazolyl,benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl or indolylradicals can be mentioned.

A more particular subject of the invention is the compounds of generalformula I_(A) as defined above in which

Ar represents the thienyl, furyl, benzothienyl, benzofuryl radical andoptionally substituted by one or more methyl, ethyl, propyl or allylradicals;

R₁ and R₂ identical or different represent a hydrogen atom or a methylor ethyl radical, or

R₁ and R₂ form with the nitrogen atom to which they are linked a

radical in which n is equal to 1 and R₃ and R′₃ identical or differentrepresent a hydrogen atom or a hydroxyl, hydroxymethyl, hydroxyethyl,methyl or ethyl radical.

More particularly, a subject of the invention is the compounds offormula I_(A) described hereafter in the examples, in particular thecompounds corresponding to the following formulae:

—N-[4-(2-thienyl)-3-methyl-tetrahydro-4H -thiopyran-4-yl]-piperidine;

—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine;

—N-[4-(2-benzothiophenyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine;

—N-[4-(2-furyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;

—N-[4-(2-benzofuranyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;

—N-[4-(5-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;

—N-[4-(4-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;

—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-hydroxy piperidine;

—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-4-hydroxy piperidine

in all the possible racemic, enantiomeric and diastereoisomeric isomerforms as well as the addition salts with mineral and organic acids orwith mineral and organic bases of said compounds.

A subject of the invention is also a preparation process for thecompounds of general formula I as defined above, characterized in thatit comprises

the reaction of a compound of formula I

 in which X″, Y″, Z″ represent a sulphur or oxygen atom or a methyleneradical, R₄ has the meaning indicated above, with an aryl magnesiumhalide of formula Ar-Mg-Hal in which Hal represents a halogen atom andAr has the meaning indicated above, in order to obtain the compound offormula 2

 in which X″, Y″, Z″, Ar and R₄ have the meanings indicated above,

the conversion of the hydroxyl radical of the alcohol of formula 2 thusobtained, to an azide of formula 3

 in which X″, Y″, Z″, Ar and R₄ have the meanings indicated above,

then the reduction of the acid azide of formula 3 in primary amine offormula 4

 in which X″, Y″, Z″, Ar and R₄ have the meaning indicated above,

and finally, if the desired compound of formula I is such that at leastone of the R₁ or R₂ radicals is different from the hydrogen atom or R₁and R₂ form a ring with the nitrogen atom to which they are linked, thetreatment of this compound of formula 4 in order to obtain the compoundof formula I which is converted into the salt if desired.

In this preparation process, the first stage which consists of obtainingthe compound of formula 2, is a standard Grignard reaction theimplementation conditions of which are known to a person skilled in theart.

The second stage allows access to azide 3 from alcohol 2. The reactiontakes place in the presence of an excess of an organic protonating agentsuch as trichloroacetic acid, an alkaline azide in a polar aproticsolvent. Preferably, the reaction takes place in the presence of anexcess of trichloroacidetic acid and sodium azidide in chloroform.

For the reduction of the azides of formula 3 to the primary amine 4,standard methods known to a person skilled in the art for the reductionof azides can be used. The reduction can therefore be carried out using,for example, Raney nickel in isopropanol at 60° C. or lithium aluminiumhydride in diethylether or tetrahydrofuran.

If in the desired compound of formula I, R₁ and R₂ form a ring with thenitrogen atom to which they are linked, the fourth stage is then acyclization; it is obtained by reacting, in a polar solvent, in analkaline medium, the compound of formula 4 with the appropriate compoundof formula Hal-(CH₂)₂—(CH₂)n-(CH₂)₂-Hal or Hal-(CH₂)—CH═CH—(CH₂)₂-Hal ofcis structure, substituted by the R₃ and R′₃ radicals, and in which n,R₃ and R′₃ have the meaning indicated above and Hal represents a halogenatom. The alkaline conditions allow the acid formed to be trapped andcan be obtained by using, potassium carbonate for example. The polarsolvent used can be chosen from methanol, acetone,hexamethylphosphoramide or sulpholane and preferablyhexamethylphosphoramide.

The primary amine of formula 4 therefore corresponds to the compound offormula I in which R₁ and R₂ represent the hydrogen atom. If in thedesired compound of formula I, R₁ and R₂ are identical or different andat least one of the two does not represent the hydrogen atom, then thecompound of formula I is a secondary or tertiary amine depending on thevalues of R₁ and R₂; these amines can be obtained from the correspondingprimary amine of formula 4 according to standard methods known to aperson skilled in the art. Thus, for example, for the preparation of thecompound of formula I in which one of the R₁ or R₂ radicals representsthe hydrogen atom and the other an alkyl radical, the correspondingprimary amine of formula 4 is reacted with the appropriate acidanhydride then the amide obtained is reduced with, for example, LiAlH4.

The different enantiomeric and diastereoisomeric isomer forms can beobtained by resolution either of the starting product or of the finalproduct according to methods known to a person skilled in the art. Forexample, the two diastereoisomers can be separated in the final stage bysimple chromatography. This separation can also be carried out afterobtaining the compounds of formula 4. The resolution can also be carriedout by using optically active acids such as tartaric or mandelic acids.

A subject of the invention is also another preparation process for thecompounds of general formula I as defined above, characterized in thatit comprises

the reaction of a compound formula 1

 in which X″, Y″, Z″ and R₄ have the meaning indicated above, in ananhydrous medium, with a compound of formula R₁R₂NH in which R₁ and R₂have the meanings indicated above, and a cyanide ion donor compound, inorder to obtain the compound of formula 5

 in which X″, Y″, Z″, R₁ and R₂ have the meanings indicated above, and

the reaction of the compound of formula 5 thus obtained, with an arylmagnesium halide of formula Ar-Mg-Hal in which Ar has the meaningindicated above and Hal represents a halogen atom, in order to obtainthe compound of formula I according to the invention.

In this second preparation process, the reaction for obtaining thecompound of formula 5 can be carried out in the presence of acetonecyanohydrin as cyanide ion doner; as a dehydration agent of the medium,anhydrous magnesium sulphate can for example be used. The reaction ispreferably carried out in a polar basic solvent such as acetamide,methylacetamide, dimethylacetamide, acetylpiperidine or piperidine, andpreferably dimethylacetamide or piperidine.

The second stage of this second preparation process is a Bruylantsreaction (P. Bruylants, Bull. Soc. Chim. Belg., 33, 467 (1924); P.Bruylants, A. Castille, Bull. Soc. Chim. Beig., 34, 261-284 (1925)). Onan experimental level, this reaction is stereospecific and leads to theintroduction of the aryl radical in equatorial position. As a result, itwill only be used for the synthesis of compounds of formula I notpossessing a particular stereochemistry.

Taking into account the lack of stereospecificity of this firstreaction. this synthesis route is preferentially used in the case whereR₄ represents a hydrogen atom.

The optional salification of the compounds of formula I is carried outaccording to the usual methods indicated hereafter in the experimentalpart.

The starting compounds of formula 1 in which R₄ represents the hydrogenatom and Y″ represents a sulphur or oxygen atom or a methylene radical,are commercial products. The other starting compounds of formula 1 inwhich R₄ represents the hydrogen atom, can be prepared according to theoutline described by T. E. Young (J. Org. Chem., 38, 1562-1566 (1973)).The starting compounds in which R₄ is different from the hydrogen atom,can be obtained from the corresponding compounds of formula 1 in whichR₄ represents the hydrogen atom, according to the substitution methodsknown to a person skilled in the art.

The compounds of the present invention have a very good affinity andselectivity for a new type of low affinity sites. The action on thesesites inhibits the neurotoxicity induced by the glutamate responsiblefor certain pathological consequences such as acute or chronicdegeneration of central or peripheral nervous system cells. Thecompounds of the present invention can thus be used in differenttherapeutic applications.

Thus the compounds of the present invention can be used to protect thecentral or peripherial nervous system cells against acute degenerationinduced by accidents such as trauma, ischemia or the action of endogenicand exogenic neurotoxic agents, directly or by means of secondarymechanisms.

The compounds can also be used to protect the central or peripherialnervous system cells against chronic degeneration induced byneurodegenerative diseases and processes of pathological aging type,dementia, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis. They can also be used as anticonvulsants or antidepressantsor to stimulate alertness, to treat states of dependency on differentsubstances such as addictive drugs.

An illustration of the pharmacological properties of the compounds ofthe invention will be found hereafter in the experimental part.

These properties make the compounds of formula I suitable forpharmaceutical use. A subject of the present Application is, asmedicaments, the compounds of formula I as defined above, in allpossible racemic, enantiomeric and diastereoisomeric isomer forms, aswell as the addition salts with pharmaceutically acceptable mineral ororganic acids or mineral or organic bases of said compounds of formulaI, as well as the pharmaceutical compositions containing, as activeingredient, at least one of the medicaments as defined above.

The invention thus relates to the pharmaceutical compositions containinga compound of the invention or an addition salt of a pharmaceuticallyacceptable acid or base of the latter, in combination with apharmaceutically acceptable support. The pharmaceutical composition canbe in the form of a solid, for example, powders, granules, tablets,gelatin capsules or suppositories. The appropriate solid supports can,for example, be calcium phosphate, magnesium stearate, talc, sugars,lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound according to theinvention can also be presented in liquid form, for example, solutions,emulsions, suspensions or syrups. The appropriate liquid supports canbe, for example, water, organic solvents such as glycerol or glycols,similarly their mixtures, in varied proportions, in water, withpharmaceutically acceptable oils or greases added to them. Sterileliquid compositions can be used for intramuscular or sub-cutaneousinjections and the sterile compositions can also be administeredintravenously. The compositions according to the invention can also beadministered by other standard routes such as oral administration.

A subject of the invention is also the use of the compounds of formulaI′ characterized in that they correspond either to formula I′A

in which

Ar′ represents a carbocyclic or heterocyclic aryl radical, monocyclicwith 5 or 6 members or constituted by condensed rings and optionallysubstituted by one or more identical or different radicals chosen fromthe halogen atoms, the hydroxyl, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, haloalkyl, hydroxyalkyl radicals, having at most 6 carbonatoms; free esterifed or salified carboxy; cyano; nitro; aminooptionally substituted by one or two identical or different alkylradicals containing at most 6 carbon atoms;

R′₁ and R′₂ identical or different represent a hydrogen atom or an alkylradical having at most 6 carbon atoms optionally substituted by one ormore identical or different radicals chosen from the hydroxyl, freeesterified or salified carboxy, cyano, nitro radicals or R′₁ and R′₂form with the nitrogen atom to which they are linked a

 radical in which n represents an integer from 0 to 2 and R₃ and R′₃identical or different represent a hydrogen atom, a halogen atom or ahydroxyl, free esterified or salified carboxy, cyano, nitro, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl radicalhaving at most 6 carbon atoms;

R′₄ has the same meaning as R₃ or R′₃;

X′, Y′ and Z′ are such that at least one represents a sulphur or oxygenatom or a methylene radical and the others represent a methyleneradical,

or one of the following formulae:

—N- [1-(2-thienyl)-cyclohexan-1-yl]-3-hydroxymethyl-piperidine,

—N-[1-(2-thienyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidine,

—N-[1-(2-benzothiophenyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidineor

—N-ethyl-1-(2-thienyl)-cyclohexylamine,

—N-[1-(2-furyl)-cyclohexan-1-yl] piperidine,

—N-[1-(2-thienyl)-cyclohexan-1-yl]-3-methyl-piperidine,

said compounds of formula I′ being in all possible racemic, enantiomericand diastereoisomeric isomer forms as well as the use of addition saltswith mineral and organic acids or with mineral and organic bases of saidcompounds of formula I′,

for the preparation of medicaments intended to protect the central orperipherial nervous system cells against acute degeneration induced byaccidents such as trauma, ischemia or the action of endogenic orexogenic neurotoxic agents, directly or by means of secondarymechanisms.

The invention also relates to the use of the compounds of formula I′ asdefined above, for the preparation of medicaments intended to protectthe central or peripherial nervous system cells against chronicdegeneration induced by neurodegenerative processes or diseases ofpathological aging type, dementia, Alzheimer's disease, Parkinson'sdisease, amyotrophic sclerosis, as well as anticonvulsants orantidepressant medicaments or medicaments to stimulate alertness, totreat states of dependancy on different substances such as addictivedrugs like cocaine.

The invention more particularly relates to the use of compounds offormula I′_(A) as defined above in which

Ar′ represents a heterocyclic aryl radical, monocyclic with 5 members orconstituted by two condensed rings and optionally substituted by one ormore identical or different alkyl or alkenyl radicals;

R′₁ and R′₂ identical or different represent a hydrogen atom or an alkylradical having at most 6 carbon atoms or R₁ and R₂ form with thenitrogen atom to which they are linked a

 radical in which n is equal to 1 and R₃ and R′₃ identical or differentrepresent a hydrogen atom or a hydroxyl, alkyl or hydroxyalkyl radicalhaving at most 6 carbon atoms, for the preparation of medicaments asdefined above.

The invention also relates more particularly to the use of the compoundsof formula I′A as defined above in which

Ar′ represents the thienyl, furyl, benzothienyl, benzofuryl radical andoptionally substituted by one or more methyl, ethyl, propyl or allylradicals;

R′₁ and R′₂, identical or different, represent a hydrogen atom or amethyl or ethyl radical, or

R₁ and R₂ form with the nitrogen atom to which they are linked a

 radical in which n is equal to 1 and R₃ and R′3, identical ordifferent, represent a hydrogen atom or a hydroxyl, hydroxymethyl,hydroxyethyl, methyl or ethyl radical, for the preparation ofmedicaments as defined above.

More particularly, a subject of the invention is the use of compounds offormula I′A and corresponding to the following formulae:

—N-[4-(2-thienyl)-3-methyl-tetrahydro-4H-thiopyran-4-yl]-piperidine;

—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine;

—N-[4-(2-benzothiophenyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine;

—N-[4-(2-furyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;

—N-[4-(2-benzofuranyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;

—N-[4-(5-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;

—N-[4-(4-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;

—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]l-3-hydroxy piperidine;

—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-4-hydroxy piperidine;

—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl] piperidine;

—N-[4-(2-thienyl)-tetrahydro-4H-pyran-4-yl] piperidine;

—N-[3-(2-thienyl)-tetrahydro-4H-thiopyran-3-yl] piperidine;

for the preparation of medicaments as defined above.

The following examples are presented in order to illustrate the aboveprocedures and must in no case be considered as a limit to the scope ofthe invention.

EXPERIMENTAL PART Example 1N-[4-(2-thienyl)-3-methyl-tetrahydro-4H-thiopyran-4-yl] piperidine

Stage 1a: 3-methyl-tetrahydro-4H-thiopyran-4-one

Diisopropylamine (8.4 ml, 60 mmole) and 74 ml of THF are introducedunder nitrogen into a 250 ml three-necked flask. nBuLi (37.5 ml, 60mmole) is introduced dropwise and agitated for an additional half-hourat 25° C. The lithium diisopropylamide solution (0.5 M) obtained iscooled down to −80° C. Tetrahydro-4H-thiopyran-4-one (6.96 g, 60 mmole)is added slowly. After half an hour, methyl iodide (5.6 ml, 90 mmole) isadded and the temperature is allowed to return to 25° C. After fivehours of agitation, a salt saturated solution of sodium bicarbonate (5%)is added, followed by decanting, the organic phase is dried over sodiumsulphate and concentrated to dryness. The orange oil obtained ischromatographed on silica eluting with an EP/AcOEt 90/10 mixture. Inthis way, a colourless oil is obtained (3.2 g).

NMR ¹H: 2.8 (m, 3H); 2.4 (m, 4H); 0.95 (d, 3H, J=6.1 Hz).

NMR ¹³C: 209.52 (C4); 47.20 (C3); 43.45 (C5); 30.07 (C2); 30.38 (C6);14.41 (CH₃)

Stage 1. b: 4-(2-thienyl)-3-methyl-tetrahydro-4H-thiopyran-4-ols

2-thienylmagnesium bromide is prepared under nitrogen from magnesium(0.9 g, 37.2 mmole), 2-bromo-thiophene (6.1 g, 37.2 mmole) and 100 ml ofanhydrous ether followed by heating at 45° C. for 3 hours, then3-methyl-tetrahydro-4H-thiopyran-4-one (4.2 g, 33 mmole) dissolved inether (50 ml) is added at ambient temperature. The reaction medium isheated for 16 hours under reflux. After cooling down, the reactionmedium is poured into 100 ml of an aqueous solution saturated in NH4Cl,followed by agitation for 30 minutes in order to destroy the magnesiumcomplex. After decanting, the aqueous phase is extracted with ether(3×50 ml) which is then neutralised by NH4OH (25%). After extractionwith ether (3×50 ml), the combined organic phases are washed with waterto neutrality, dried over Na₂SO₄, filtered and concentrated to dryness.The green oil obtained (7.6 g) is chromatographed on silica eluting withan EP/EA (90/10) mixture. A limpid oil is thus obtained.

Rf (silica, eluent EP/EA 60/40): 0.4

GC/MS (90-250° C. (10° C./min)):

Tr=14.40 min (majority diastereoisomer: 87%)

Tr=14.71 min (minority diastereoisomer: 13%)

NMR ¹³C: majority diastereoisomer: 153.65 (C2′); 126.88-121.80 (C3′ toC5′); 74.52 (C4); 43.33 (C5); 42.68 (C3); 30.67 (C2); 23.89 (C6); 15.86(CH₃). minority diastereoisomer: 153.0 (C2′); 126.43-122.98 (C3′ toC5′); 73.33 (C4); 40.25 (C3); 33.84 (C5); 30.17 (C2); 23.89 (C6); 15.04(CH₃).

Stage 1. c: 4-(2-thienyl)-3-methyl-tetrahydro-4H-thiopyran-4-yl-azides

Trichloracetic acid (15.1 g, 92.4 mmole) is dissolved in chloroform (100ml). Sodium azide (4 g, 61.7 mmole) is added and the medium is cooleddown to 10° C. The diastereoisomer alcohols obtained according to theprevious stage (6.6 g, 30.8 mmole) dissolved in chloroform (50 ml) areadded dropwise. The reaction medium is agitated for 72 hours whilstmaintaining the temperature at 10-12° C. A solution of ammoniumhydroxide (10%) is then added until neutralisation, then the aqueousphase is extracted with dichloromethane (3×100 ml). The organic phase iswashed with water (200 ml), dried over Na₂SO₄ and concentrated todryness. In this way, a brown oil is obtained (6.8 g) which is then usedwithout further purification.

Rf (silica, eluent EP/EA 60/40): 0.37

GC/MS (60-250° C.(10° C./min)):

Tr=18.31 min (majority diastereoisomer: 72%)

Tr=18.08 min (minor diastereoisomer: 28%)

Stage 1. d: 4-(2-thienyl)-3-methyl-tetrahydro-4H-thiopyran-4-yl-amines

Lithium aluminium hydride (0.87 g, 23 mmole) in THF is introduced into a100 ml three-necked flask at 0° C. The azide mixture obtained in theprevious stage (5.5 g, 23 mmole) dissolved in 30 ml of THF is addeddropwise. The reaction medium is agitated for 24 hours at ambienttemperature. The minimum amount of ammonium hydroxide (10%) is addedvery slowly in order to destroy the excess LiAlH₄, followed by filteringon celite, the precipitate is washed with dichloromethane (300 ml) andconcentrated to dryness. The brown oil obtained is taken up in ether andextracted with a solution of HCl (10%) (3×100 ml). The aqueous phase isthen neutralised with ammonium hydroxide (20%) and extracted with ether(3×100 ml). The organic phase is washed with water, dried over MgSO₄ andconcentrated to dryness. The product obtained is purified bychromatography on silica eluting with an EP/EA 50/50 mixture. In thisway, a colourless oil is obtained (3.7 g).

Rf (silica, eluent EP/EA 60/40): 0.20 (majority) and 0.25 (minority)

GC/MS (90-250° C. (10° C./min)):

Tr=24.15 min (majority diastereoisomer: 62.5%)

Tr=23.77 min (minority diastereoisomer: 37.5%)

NMR ¹³C (majority): 155.11 (C2′); 125.99-121.94 (C3′ to C5′); 54.80(C4); 40.72 (C3); 34.51 (C5); 30.66 (C2); 23.44 (C6); 15.34 (CH₃). NMR¹³C (minority): 156.60 (C2′); 126.41-121.26 (C3′ to C5′); 55.84 (C4);43.92 (C5); 42.40 (C3); 30.04 (C2); 23.35 (C6); 15.97 (CH₃).

Stage 1. e: N-[4-(2-thienyl)-3-methyl-tetrahydro-4H-thiopyran-4-yl]piperidines

The amine mixture of Stage 1d above (4.5 g, 21 mmoles) is dissolved inHMPT (50 ml). Potassium carbonate (5.8 g, 42 mmoles) and1,5-dibromopentane (3.6 ml, 26.2 mmoles) are added. The medium isagitated under nitrogen at 60° C. for 48 hours. After cooling down, thissolution is poured into water (200 ml) and extracted with ether (3×100ml). As previously, an acid-base washing is carried out, followed byre-extraction with ether, the ethereal phase is washed with water,followed by drying over magnesium sulphate and concentration to dryness.The yellow oil obtained (6.2 g) is purified by chromatography on silicaeluting with an EP/EA (90/10) mixture. In this way, the twodiastereoisomers are obtained separately: the majority diastereoisomer(2 g, 34%) and the minority diastereoisomer (0.7 g, 12%), both in theform of a white solid.

Rf (silica, eluent EP/AP 90/10): 0.6 (trans), 0.4 (cis)

CPV:

Tr (majority)=18.15 min and Tr (racemic)=19.75 min

Tr (minority)=18.46 min and Tr (racemic)=18.95 min

NMR ¹³C (majority): 145.88 (C2′); 125.80-122.41 (C3′ to C5′); 61.51(C4); 45.96 (Cα); 33.26 (C3); 29.47 (C5); 28.38 (C2); 26.90 (Cβ); 25.03(C6); 22.93 (Cγ); 15.10 NMR ¹³C (minority): 142.70 (C2′); 126.23-122.76(C3′ to C5′); 62.08 (C4); 45.59 (Cα); 33.55 (C3); 32.88 (C5); 30.64(C2); 26.87 (Cβ); 25.38 (C6); 25.03 (Cγ); 13.41 (CH₃).

Example 2(±)-N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine

Stage 2a: 4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile

Magnesium sulphate (9.6 g, 80 mmoles), DMA (2 g, 23 mmoles),(±)-3-methylpiperidine (4 g, 40 mmoles), tetrahydro-4H-thiopyran-4-one(2.3 g, 20 mmoles) and acetone cyanohydrin (1.7 g, 20 mmoles) areintroduced in succession into a 250 ml two-necked flask. The reactionmedium is agitated for 48 hours at 45° C. After cooling down to ambienttemperature, the pasty mixture obtained is placed on ice (approximately150) and agitated for 30 minutes. Extraction with ether is then carriedout (3×80 ml), the combined organic phases are washed with water (100ml), followed by drying over Na₂SO₄, filtering and concentration todryness. A brown oil is thus obtained (4.5 g, 20 mmoles) constituted bya mixture of expected product with approximately 4% of amino nitriteoriginating from acetone and 7% of the remainingtetrahydro-4H-thiopyran-4-one. The product is then used without furtherpurification.

NMR ¹³C: 118.3 (CN); 59.43(C4); 54.1 (Cα); 46.42 (Cα′); 34.3 (C3*); 34.2(C5*); 32.1 (Cγ); 30.9; 25.1 (C2-C6); 22.8 (Cβ′); 19.3 (CH₃).

Stage 2b:(±)-N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine

2-thienylmagnesium bromide is prepared under nitrogen from magnesiumturnings (1 g, 40 mmoles), 2-bromothiophene (6.52 g, 40 mmoles) and 150ml of anhydrous ether. The ether is heated under reflux for 3 hours thenthe aminonitrile obtained according to the previous stage (2.25 g, 10mmoles) is added at ambient temperature. The reaction medium is heatedfor 20 hours under reflux. After the usual treatment, a brown oil isobtained which is chromatographed on 100 g of alumina eluting with anEP/EA (95/5) mixture. In this way, a colourless oil is obtained (1.6 g).

NMR ¹³C: 146.6 (C2′); 126,0-122.7 (C3′ to C5′); 58.2 (C4); 53.35 (Cα);45.5 (Cα′); 37.1 (C3*); 36.8 (C5*); 33.2 (Cβ′); 31.8 (Cβ); 23.4 (C2-C6);22.5 (Cγ); 19.3 (CH₃).

The corresponding hydrochloride is prepared by treatment of the base inhydrochloric ether for 3 hours. After filtration and abundant rinsingwith anhydrous ether, a white powder is obtained (1.42 g). M.p.=168° C.

NMR ¹³C: 134.5 (C2′); 130,3-127.9 (C3′ to C5′); 68.9 (C4); 52.3 (Cα);46.2 (Cα′) 33.4 (C3*); 33.2 (C5*); 30.5 (Cβ′); 28.2 (Cβ); 24.9 (C2-C6);22.1 (Cγ); 18.9 (CH₃).

Example 3S-(−)-N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine

Stage 3a: S-(+)-3-methyl-piperidine

(+) mandelic acid (45.64 g, 0.3 mol) is dissolved in 300 ml of warmethyl acetate. 3-methylpiperidine (29.8 g, 0.3 mol) is added underagitation and the solution allowed to return to ambient temperature.After 24 hours, the salt obtained is filtered and rinsed with anEA/AcOEt (1/1) mixture then recrystallized 3 times from AcOEt. In thisway, the (S)-(+)-3-methylpiperidine mandelate salt (22.7 g) is obtained.M.p.=120-122° C; αD=+58.0° (methanol, c=1.0).

These crystals are taken up in 50 ml of an aqueous solution of soda at25% then the solution is extracted with ether (3×50 ml). The combinedorganic phases are washed with a saturated solution of NaCl, dried overMgSO₄, then concentrated. The oil obtained is distilled to atmosphericpressure in order to produce a colourless liquid (7.1 g). M.p.=92-97° C.

NMR ¹³C=53.2 (C2); 45.1 (C6); 32.2 (C4); 30.6 (C3); 25.2 (C5); 18.0(CH₃).

Stage 3b:S-4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile

The operating method is identical to that illustrated in Stage 2a usingS-(−)-3-methylpiperidine instead of (±)-3-methylpiperidine. Stage 3c:S-(−)-N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine

The operating method is identical to that illustrated in Stage 2b usingS-4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile insteadof (±)-4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile. Acolourless oil is obtained (1.8 g) which crystallizes when cold.M.p.=53-55° C.

The hydrochloride is obtained according to the operating methoddescribed in Stage 2b.

M.p.=169-171° C. αD=−10° (methanol, c=1.0)

Example 4R-(+)-N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine

Stage 4a: R-(−)-3-methyl-piperidine

The crystallization and recrystallization filtrates of theS-(+)-3-methyl-piperidine mandelic salts from the previous Stage 3a arerecombined and treated with 100 ml of an aqueous solution of soda (25%).After 30 minutes under agitation, this aqueous phase is extracted withether (4×50 ml). The combined organic phases are washed with a saturatedsolution of NaCl (100 ml), dried over MgSO4, then concentrated. In thisway, a liquid enriched in (R)-(+)-3-methylpiperidine is obtained whichis added to 30 g of (−) mandelic acid dissolved in 180 ml of warm ethylacetate. After 24 hours, the salt obtained is filtered and rinsed withan EA/AcOEt (1/1) mixture then recrystallized twice from ethyl acetate.The R-(−)-3-methyl-piperidine mandelate salt is obtained in the form ofwhite crystals (17 g).

M.p.=121-123° C.; αD=−56.5° (methanol, c=1.0)

These crystals are taken up in 50 ml of a 25% aqueous soda solution thenthe solution is extracted with ether (3-50 ml). The combined organicphases are washed with a saturated solution of NaCl, dried over MgSO₄,then concentrated. The oil obtained is distilled at atmospheric pressurein order to produce a colourless liquid (5.2 g).

Stage 4b:R-4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile

The operating method is identical to that illustrated in Stage 2a, usingR-(+)-3-methylpiperidine instead of (±)-3-methylpiperidine.

Stage 4c:R-(+)-N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine

The operating method is identical to that illustrated in Stage 2b, usingR-4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile insteadof (±)-4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile. Acolourless oil is obtained (1.65 g) which crystallizes when cold.M.p.=54-56° C.

The hydrochloride is obtained according to the operating methoddescribed in Stage 2b.

M.p.=170-172° C. αD=+12° (methanol, c=1.0)

Example 5(±)-N-[4-(2-benzothiophenyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine

4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile (2 g, 8.9mmoles) dissolved in 50 ml of anhydrous ether is introduced dropwiseinto a 2-benzothiophenylmagnesium bromide (44.7 mmoles) solution. Etheris heated under reflux for 20 hours. After the usual treatment, a brownoil is obtained (1.7 g) which is chromatographed on 60 g of aluminaeluting with an EP/EA (95/5) mixture. In this way, a white solid isobtained (1.2 g, 40%).

M.p.=90-92° C. NMR ¹³C: 147.99 (C2′); 139.19 (C7′a); 138.32 (C3′a);123.90 to 119.96 (C3′ to C7′) 58.88 (C4); 53.45 (Cα); 45.65 (Cα′); 36.78(C3*); 36.52 (C5*); 33.17 (Cβ′); 31.85 (Cβ); 26.14 (Cγ); 23.52 (C2-C6);19.77 (CH₃).

The corresponding hydrochloride is prepared. M.p.=160° C.

NMR ¹³C: 139.45 (C2′); 138.63 (C7′a); 135.04 (C3′a); 127.89 to 121.86(C3′ to C7′); 69.26 (C4); 52.75 (Cα); 46.72 (Cα′); 33.48 (C3*); 33.29(C5*); 30.57 (Cβ′); 28.41 (Cβ); 25.06 (C2-C6); 22.21 (Cγ); 18.92 (CH₃).

Example 6R-(+)-N-[4-(2-benzothiophenyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine

The operating method is identical to that of Example 5 usingR-4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile insteadof 4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile. Thesame quantites of reagents are used. Colourless crystals are obtained(1.85 g).M.p.=90-92° C.

Characteristics of the corresponding hydrochloride:

M.p.=158-165° C.; αD=+27.2° (methanol, c=1.0)

Example 7S-(−)-N-[4-(2-benzothiophenyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine

The operating method is identical to that in Example 5 usingS-4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile insteadof 4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile. Thesame quantites of reagents are used. Colourless crystals are obtained(1.2 g).M.p.=91-93° C.

Characteristics of the corresponding hydrochloride:

M.p.=162-168° C.; αD=−23.6° (methanol, c=1.0).

Example 8 N-[1-(2-thienyl)-cyclohexan-1-yl]-3-hydroxymethyl-piperidine

Stage 8a:1-[1-(3-hydroxymethyl-piperidino)-cyclohexan-1-yl]-carbonitrile

It is prepared from MgSO₄ (9 g, 75 mmoles), (2.2 g, 25 mmoles),3-hydroxymethyl-piperidine (5.8 g, 38 mmoles), cyclohexanone (2.5 g, 25mmoles) and acetone cyanohydrin (2.2 g, 25 mmoles) as describedpreviously in Stage 2a. After treatment of the reaction, a white solidis obtained (4.5 g).

NMR ¹³C: 118.89 (CN); 64.94 (CH2OH); 60.93 (C1); 50.17 (Cα); 47.07(Cα′); 34.75 (Cβ); 33.72 (C2*); 33.60 (C6*); 26.79 (Cγ); 24.65 (C3-C5);21.83 (C4).

Stage 8b: N-[1-(2-thienyl)-cyclohexan-1-yl]-3-hydroxymethyl-piperidine

2-thienylmagnesium bromide is prepared under nitrogen from magnesium(0.66, 27.2 mmoles), 2-bromothiophene (4.4 g, 9.5 mmoles) and 80 ml ofanhydrous ether followed by heating at 45° C. for 3 hours, then1-[1-(3-hydroxymethyl-piperidino)-cyclohexan-1-yl]-carbonitrile (2 g, 9mmoles) dissolved in ether is added at ambient temperature. The reactionmedium is heated for 20 hours under reflux. After treatment of thereaction, 2.1 g of a yellow oil is obtained which is chromatographed onalumina eluting with an EP/EA (50/50) mixture. In this way, a colourlessoil is obtained (1.4 g).

NMR ¹³C: 145.45 (C2′); 125.84 to 122.76 (C3′ to C5′); 66.66 (CH₂OH);60.06 (C1); 49.26 (Cα); 46.08 (Cα′); 38.44 (Cβ); 35.89 (C2*); 35.69(C6*); 27.73 (Cβ′); 25.22 (Cγ); 24.70 (C3-C5); 22.08 (C4).

Characteristics of the corresponding hydrochloride:

M.p.=176-178° C. NMR ¹³C: 135.76 (C2′); 130.57 to 127.92 (C3′ to C5′);69.74 (CH2OH); 64.20 (C1); 49.69 (Cα); 46.85 (Cα′); 36.60 (Cβ); 33.37(C2*); 33.00 (C6*); 25.27 (Cβ′); 23.97 (Cγ); 23.03 (C3-C5); 22.21 (C4).

Example 9 N-[4-(2-furyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine

Stage 9a: 4-piperidino-tetrahydro-4H-thiopyran-4-carbonitrile

Magnesium sulphate (9.3 g, 77.4 mmoles), DMA (2.25 g, 25.8 mmoles),piperidine (4.4 g, 51.6 mmoles), tetrahydro-4H-thiopyran-4-one (3 g,25.8 mmoles) and acetone cyanhydrin (2.2 g, 25.8 mmoles) are introducedin succession into a 250 ml two-necked flask. The reaction medium isagitated for 48 hours at 45° C.

After cooling down to ambient temperature, the mixture obtained isplaced on ice (approximately 100 g) and agitated for 30 minutes.Extraction with ether (3×80 ml) is then carried out, the combinedorganic phases are washed with water (100 ml), dried over Na₂SO₄,filtered and concentrated to dryness. An orange oil is obtained (5.3 g,25.2 mmoles) which is then used without particular purification.

NMR ¹³C: 118.34 (CN); 59.61 (C4); 46.985 (Cα); 34.215 (C3-C5); 25.72(C2-C6); 23.77 (Cβ); 22.76 (Cγ).

Stage 9b: N-[4-(2-furyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine

An MgBr₂ solution is prepared by adding 1,2-dibromo-ethane (6.76 g, 36mmoles) diluted in 80 ml of anhydrous ether to magnesium turnings (0.88g, 36 mmoles) dropwise and under nitrogen. The solution is maintained atambient temperature for 2 hours.

A 2-lithio-furan solution is prepared simultaneously at −20° C. andunder nitrogen by adding a 1.6 M solution of n-butyllithium in hexane(28 ml, 45 mmoles) dropwise to a furan mixture (3.1 g, 45 mmoles). Thismixture is heated for 2 hours under reflux.

This solution is decanted at ambient temperature. The aminonitrile ofStage 9a (1.9 g, 9 mmoles) dissolved in 50 ml of anhydrous ether isadded dropwise to the 2-furylmagnesium bromide solution. The ether isheated under reflux for 16 hours. After the usual treatment, a brownsolid is obtained (1.8 g) which is chromatographed on 60 g of aluminiumeluting with an EP/EA (98/2) mixture. In this way, a white solid isobtained (1.6 g, 71%).

M.p.=79-81° C. NMR ¹³C: 156.49 (C2′); 141.05 (C5′); 109.27 (C3′); 106.10(C4′); 57.47 (C4); 46.44 (Cα); 33.57 (C3-C5); 26.58 (C2-C6); 24.55 (Cγ);23.30 (Cβ).

Characteristics of the corresponding hydrochloride:

M.p.=171-173° C. NMR ¹³C: 145.25 (C2′); 143.49 (C5′); 113.71 (C3′);110.74 (C4′); 66.84 (C4); 46.74 (Cα); 30.25 (C3-C5); 24.52 (C2-C6);21.96 (Cβ); 21.33 (Cγ).

Example 10 N-[4-(2-benzofuryl)-tetrahydro-4H-thiopyran-4-yl]-piperidine

The preparation process is identical to that in Stage 9b but using a2-lithio-benzofuran solution instead of a 2-lithio-furan solution.

After the usual treatment, a yellow solid is obtained which ischromatographed on alumina eluting with an EP/EA (98/2) mixture. In thisway, a white solid is obtained (67%).

M.p.=109-111° C. NMR ¹³C: 159.78 (C2′); 154.0 (C7′a); 127.83 (C3′a);123.42 to 102.8 (C3′ to c7′); 57.76 (C4); 46.62 (Cα); 33.78 (C3-C5);26.81 (C2-C6); 24.64 (Cγ); 23.17 (Cβ).

Characteristics of the corresponding hydrochloride:

M.p.=171-173° C. NMR ¹³C: 154.18 (C2′); 147.88 (C7′a); 126.65 (C3′a);125.80 to 111.07 (C3′ to C7′); 67.83 (C4); 47.55 (Cα); 30.77 (C3-C5);24.99 (C2-C6); 22.47 (Cβ); 24.64 (Cγ).

Example 11N-[4-(5-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine

The preparation process is identical to that of Stage 9b but using a2-lithio-5-methyl-thiophene solution instead of a 2-lithio-furansolution.

After the usual treatment, a yellow solid is obtained which ischromatographed on alumina eluting with an EP/EA (98/2) mixture. In thisway, a white solid is obtained (67%).

M.p.=93-95° C. NMR ¹³C: 144.04 (C2′); 136.95 (C5′); 124.05 (C3′); 123.05(C4′); 58.44 (C4); 45.96 (Cα); 36.65 (C3-C5); 26.74 (C2-C6); 24.88 (Cγ);23.37 (Cβ); 15.09 (CH₃).

Characteristics of the corresponding hydrochloride:

M.p.=160-162° C. NMR ¹³C: 142.88 (C2′); 131.34 (C5′); 130.25 (C3′);125.82 (C4′); 68.83 (C4); 46.47 (Cα); 32.89 (C3-C5); 24.68 (C2-C6);22.27 (Cβ); 21.69 (Cγ); 14.75 (CH₃).

Example 12N-[4-(4-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine

The preparation process is identical to that of Stage 9b but using a2-lithio-4-methyl-thiophene solution instead of a 2-lithio-furansolution.

After the usual treatment, a brown solid is obtained which ischromatographed on alumina eluting with an EP/EA (90/10) mixture. Inthis way, a white solid is obtained (55%).

M.p.=89-91° C. NMR ¹³C: 146.04 (C2′); 136.32 (C4′); 125.63 (C3′); 118.05(C5′); 58.34 (C4); 45.95 (Cα); 36.66 (C3-C5); 26.74 (C2-C6); 24.68 (Cγ);23.32 (Cβ); 15.78 (CH₃).

Characteristics of the corresponding hydrochloride:

M.p.=144-146° C. NMR ¹³C: 138.86 (C2′); 134.17 (C5′); 132.68 (C3′);123.93 (C4′); 69.43 (C4); 47.17 (Cα); 33.57 (C3-C5); 25.21 (C2-C6);22.84 (Cβ); 21.14 (Cγ); 15.61 (CH₃).

Example 13 N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-hydroxypiperidine

Stage 13a:4-(3-hydroxypiperidino)-tetrahydro-4H-thiopyran-4-carbonitrile

3-hydroxy-piperidine hydrochloride (6.5 g, 47.3 mmoles) in 30 ml ofwater is introduced into a 100 ml two-necked flask. Potassium cyanide(1.85 g, 35.5 mmoles) is added and tetrahydro-4H-thiopyran-4-one (2.7 g,23.6 mmoles) is introduced dropwise. The pH of the medium is adjusted to11 with a few drops of soda (10%). After 24 hours under agitation atambient temperature, extraction with ether (3×80 ml) is carried out, thecombined organic phases are washed with water (100 ml), dried overNa₂SO₄, filtered and concentrated to dryness. In this way, a colourlessoil is obtained (3.9 g, 17.2 mmoles).

NMR ¹³C: 117.87 (CN); 66.25 (Cβ); 59.19 (C4); 53.20; 45.96 (Cα′); 33.94(C3-C5); 31.79 (Cγ); 22.70 (C2-C6); 21.90 ( (Cβ′).

Stage 13b: N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-hydroxypiperidine

2-thienylmagnesium bromide is prepared under nitrogen starting frommagnesium (1.3 g, 53.2 mmoles), 2-bromothiophene (8.7 g, 53.2 mmoles)and 100 ml of anhydrous ether followed by heating at 45° C. for 3 hours,then the aminonitrile obtained in Stage 13a (3 g, 13.3 mmoles) dissolvedin ether is added at ambient temperature. The reaction medium is heatedfor 20 hours under reflux. After treatment of the reaction, 2.3 g of abrown oil is obtained which is chromatographed on silica eluting with anEP/EA (30/70) mixture. In this way, a white solid is obtained (42%).

M.p.=84-87° C. NMR ¹³C: 145.82 (C2′); 126.71 to 123.13 (C3′ to C5′);66.83 (Cβ); 58.23 (C4); 52.52 (Cα); 45.89 (Cα′); 36.40 (C3-C5); 32.18(Cγ); 23.40 (C2-C6); 22.36 (Cβ′).

Characteristics of the corresponding hydrochloride:

M.p.=169-172° C. NMR ¹³C: 134.26 (C2′); 130.78 to 128.29 (C3′ to C5′);69.69 (C4); 63.75 (Cβ); 51.31 (Cα); 46.18 (Cα′); 34.10 (C3-C5); 31.22(Cγ); 25.28 (C2-C6); 20.38 (Cβ′).

Example 14 N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-4-hydroxypiperidine

Stage 14a:4-(4-hydroxypiperidino)-tetrahydro-4H-thiopyran-4-carbonitrile

It is prepared from MgSO₄ (7.2 g, 60 mmoles), DMA (2.62 g, 30 mmoles),4-hydroxy-piperidine (3.03 g, 20 mmoles), tetrahydro-4H-thiopyran-4-one(2.32 g, 20 mmoles) and acetone cyanhydrin (1.7 g, 20 mmoles). Aftertreatment of the reaction, a white solid is obtained (4.7 g) which iscrystallized from anhydrous ether. In this way, white crystals areobtained (3.6 g, 79%). M.p.=79-81° C.

NMR ¹³C: 118.28 (CN); 66.67 (Cγ); 59.42 (C4); 43.87 (Cα); 33.96(C3-C5*); 34.33 (Cβ*); 22.91 (C2-C6).

Stage 14b: N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-4-hydroxypiperidine

2-thienylmagnesium bromide is prepared under nitrogen from magnesium(0.45 g, 18.5 mmoles), 2-bromothiophene (3 g, 18.5 mmoles) and 50 ml ofanhydrous ether followed by heating at 45° C. for 3 hours, then theaminonitrile obtained in Stage 14a (1.4 g, 6.2 mmoles) dissolved inether is added at ambient temperature. The reaction medium is heated for20 hours under reflux. After treatment of the reaction, 1.5 g of a brownsolid is obtained which is chromatographed on alumina eluting withanhydrous ether. In this way, a white solid is obtained (0.85 g,49%).

M.p.=145-148° C. NMR ¹³C (D₂O): 146.19 (C2′); 126.07 to 122.98 (C3′ toC5′); 68.18 (Cγ); 58.24 (C4); 42.67 (Cα); 36.92 (C3-C5*); 35.19(Cβ*);23.40 (C2-C6).

Characteristics of the corresponding hydrochloride:

M.p.=182-185° C. NMR ¹³C: 136.63 (C2′); 134.19 to 130.98 (C3′ to C5′);72.05 (C4); 67.53 (Cγ); 48.04 (Cα); 36.71 (C3-C5); 33.87 (Cβ); 27.45(C2-C6).

Example 15 N-[1-(2-thienyl)-cyclohexan-1-yl]-4-hydroxy-3-methylpiperidine

Stage 15a: ethyl N-benzoyl-4-piperidone-3-carboxylate

Benzamide (12.1 g, 0.1 mmoles) in 200 ml of toluene is introduced into a250 ml three-necked flask of 250 ml under nitrogen, and sodium hydride(4 g, 0.1 moles) is added, followed by heating for one hour underreflux, then cooling down to 0° C., and ethyl acrylate (32.6 ml, 0.3moles) is poured rapidly. The reaction medium is agitated for 24 hoursat 60° C., followed by cooling down to 0° C., and 100 ml of ice-cooledwater is added. After ½ hour under agitation, the two phases aredecanted and the aqueous phase is washed with 50 ml of ether. Theaqueous phase is acidified to pH 3 then extracted with dichloromethane(3×50 ml). The combined organic phases are dried over Na₂SO₄ andconcentrated to dryness. In this way, a yellow oil is obtained which ischromatographed on silica eluting rapidly with anhydrous ether. In thisway, a slightly redColoured oil is obtained (9.4 g, 34%) having tracesof benzamide.

NMR ¹³C: 201.63 (C4); 197.5 (C4enol); 170.89 and 170.4(CO amide andester); 135.25 to 126.87 (Caromatics); 95.73 (C3enol); 61.4 and 60.46(CH₂ enol and ketone); 56.01 (C3); 41.05 (C6); 34.55 (C2); 28.78 (C5);13.95 and 13.76 (CH₃ enol and ketone).

Stage 15b: ethyl N-benzoyl-4-piperidone-3-carboxylate

The mixture constituted by the keto-ester in Stage 15a (9.3 g, 33.8mmoles) and sodium hydride (1.35 g, 34 mmoles) in 50 ml ofdimethoxyethane is heated under reflux for 2 hours under agitationfollowed by cooling down to 0° C., and methyl iodide (5.2 ml, 84 mmoles)is added. The reaction medium is heated fog 40 hours at 60° C. followedby concentrating to dryness, and the residue is taken up in water (100ml). Extraction with dichloromethane (3×50 ml) is carried out, thecombined organic phases are washed with 50 ml of NaOH (5%), 50 ml of HCl(5%) and 50 ml of water, followed by drying over Na₂SO₄ andconcentrating to dryness. The brown oil obtained (9.4 g) ischromatographed on silica eluting with anhydrous ether. A slightlyyellow oil is obtained (7.7 g, 79%).

NMR ¹³C: 203.89 (C4); 170.54 (CO amide and ester); 134.76 to 126.87(Caromatics); 61.56 (CH2Et); 57.11 (C3); 39.05 (C6); 17.15 (CH₃); 13.60(CH₃Et).

Stage 15c: 3-methyl-4-piperidone hydrochloride

The compound of Stage 15b (7.7 g, 26.6 moles) is heated under reflux ofan aqueous solution of HCL (6N) for 72 hours. The precipitate of benzoicacid formed is filtered, the aqueous phase is extracted with ether (3×50ml) and the aqueous phase concentrated to dryness. The brown solidobtained is crystallized from ethanol and in this way white crystals areobtained (2.85 g, 72%). M.p.=180-182° C.

NMR ¹³C: 210.38 (C4); 54.58 (C2); 47.67 (C6); 47.01 (C3); 42.98 (C5);11.18 (CH₃).

Stage 15d: 3-methyl-4-piperidol

The compound of Stage 15c (2.85 g, 19 mmoles) and 30 ml of methanol areintroduced into a 100 ml three-necked flask. 7.6 ml of a soda solution(5%) is introduced dropwise. After ½ hour under agitation, a solution ofsodium borohydride (2.46 g, 6.5 mmoles) in 30 ml of methanol is pouredin. The reaction medium is agitate d for 4 hours at ambient temperature.The medium is cooled down to 0° C., a few drops of an HCl solution areadded, followed by concentrating to dryness. The yellow solid obtainedis taken up in warm ethanol and the product is precipitated by adding afew drops of ether. The precipitate is filtered and in this way a whitesolid (1.9 g, 87%) is obtained. M.p.=169-1709C.

NMR ¹³C (D₂O):

Majority diastereoisomer: 73.24 (C4); 50.75 (C2); 45.69 (C6); 38.45(C3); 32.92 (C5);16.8 (CH₃).

Minority diastereoisomer: 67.94 (C4); 46.97 (C2); 41.32 (C6); 34.89(C3); 31.29 (C5);16.47 (CH₃).

Stage 15e: 3-(4-hydroxy-3-metlyl-piperidino)-cyclohexan-1-carbonitrile

The compound of Stage 15d (0.8 g, 7 mmoles) in 10 ml of water isintroduced into a 50 ml two-necked flask. Cyclohexanone (2.7 g, 23.6mmoles) and a few drops of HCl are added in order to adjust the pH to 3.Potassium cyanide (0.47 g, 7.3 mmoles) is then added. The pH of themedium is then close to 11. After 24 hours under agitation at ambienttemperature, extraction with dichloromethane is carried out, followed bydrying over Na₂SO₄, filtering and concentrating to dryness. In this way,a colourless oil is obtained (1.43 g, 6.4 mmoles) representing only oneof the two diastereoisomers.

NMR ¹³C: 118.97 (CN); 73.69 (Cγ); 60.57 (C1); 52.43 (Cα); 45.37 (Cα′);38.57 (Cβ); 34.22 (Cβ′*); 33.98 (C2-C6*); 33.87 (C4*); 21.91 (C3-C5);15.61 (CH₃).

Stage 15f: N-[1-(2-thienyl)-cyclohexan-1-yl]-4-hydroxy-3-methylpiperidine

2-thienylmagnesium bromide is prepared under nitrogen from magnesium(0.38 g, 15.7 mmoles), 2-bromothiophene (2.57 g, 15.7 mmoles) and 60 mlof anhydrous ether. The reaction medium is heated at 45° C. for 3 hours,then the aminonitrile obtained in Stage 15e (0.7 g, 3.15 mmoles)dissolved in THF is added at ambient temperature. The reaction medium isheated for 20 hours under reflux. After treatment of the reaction, abrown oil is obtained which is chromatographed on alumina eluting withanhydrous ether. In this way, a white solid is obtained (0.48 g, 54%).

NMR ¹³C: 146.14 (C2′); 125.86 to 122.61 (C3′ to C5′); 74.76 (Cγ); 59.34(C1); 51.17 (Cα); 43.98 (Cα′); 39.36 (Cβ); 36.0 (C3-C5); 25.85 (C4*);21.96 (C3-C5*); 15.75 (CH₃).

Characteristics of the corresponding hydrochloride:

NMR ¹³C: 135.09 (C2′); 129.98 to 127.55 (C3′ to C5′); 70.60 (Cγ); 69.00(C1); 50.59 (Cα); 45.30 (Cα′); 35.37 (Cβ); 32.80 (C3-C5); 30.77 (C2-C6);23.43 (C4); 22.53 (C3-C5); 15.06 (CH₃).

Example 16 N-[1-(2-benzothiophenyl)-cyclohexan-1-yl]-4-hydroxy-3-methylpiperidine

The aminonitrile of Stage 15e (0.7 g, 3.15 mmoles) dissolved in 50 ml ofanhydrous ether is introduced dropwise into a 2-benzothiophenylmagnesiumbromide solution (15.75 mmoles). The reaction medium is heated underreflux of the ether for 16 hours. After the usual treatment, a yellowoil (0.85 g) is obtained which is chromatographed on alumina elutingwith an EP/EA (20/80) mixture. In this way, a white solid is obtained(0.74 g, 71%).

M.p.=120-122° C. NMR ¹³C: 147.60 (C2′); 139.44 (C7′a); 138.64 (C3′a);123.77 to 120.44 (C3′ to C7′); 74.89 (Cγ); 59.98 (C1); 51.29 (Cγ); 44.16(Cα′); 39.55 (Cβ); 33.84 (C2-C6); 35.27 (Cβ′); 25.86 (C4); 22.14(C3-C5); 15.85 (CH₃).

Characteristics of the corresponding hydrochloride:

M.p.=170-172° C. NMR ¹³C: 139.60 (C2′); 139.02 (C7′ and C3′a); 126.16 to120.02 (C3′ to C7′); 71.85 (Cγ): 65.66 (C1); 51.33 (Cα); 45.66 (Cα′);36.54 (Cβ); 33.58 (C2-C6); 31.99 (Cβ′); 24.12 (C4); 22.80 (C3-C5); 15.54(CH₃).

Example 17 N-ethyl-1-(2-thienyl)-cyclohexylamine

Stage 17a: 1-(2-thienyl)-cyclohexanol

2-thienylmagnesium bromide is prepared under nitrogen from magnesium(2.92 g, 120 mmoles), 2-bromothiophene (19.6 g, 120 mmoles) and 200 mlof anhydrous ether. The reaction medium is heated at 45° C. for 3 hours,then cyclohexanone (7.84 g, 80 mmoles) dissolved in ether is added atambient temperature. The reaction medium is heated for 16 hours underreflux. After cooling down, the reaction medium is poured into 100 ml ofa saturated aqueous solution of NH₄Cl, followed by agitation for ½ hourin order to destroy the magnesium complex, decanting and the aqueousphase is extracted with ether (3×50 ml). An acid-base extraction iscarried out with an aqueous HCl solution at 15% (3×50 ml) which is thenneutralised by NH₄OH (25%). After extraction with ether (3×50 ml), thecombined organic phases are washed with water until neutralised, driedover Na₂SO₄, filtered and concentrated to dryness. The brown oilobtained is chromatographed on silica eluting with an EP/EA (70/30)mixture. In this way, a slightly yellow limpid oil is obtained (12.1 g,83%)

NMR ¹³C: 153.52 (C2′); 128.38 to 121.78 (C3′ to C5′); 71.78 (C1); 39.73(C2-C6); 25.2 (C4); 22.15 (C3-C5).

Stage 17b: 1-(2-thienyl)-cyclohexylazide

Trichloracetic acid (31.9 g, 195 mmoles) is dissolved in chloroform (200ml). Sodium azide (8.45 g, 130 mmoles) is added and the medium is cooleddown to 10° C. The alcohol obtained in Stage 17a (11.8 g, 65 mmoles)dissolved in chloroform (50 ml) is added dropwise. The reaction mediumis agitated for 48 hours whilst maintaining the temperature at 10-12° C.A solution of ammonium hydroxide (10%) is then added untilneutralisation, then the aqueous phase is extracted with dichloromethane(3×100 ml). The organic phase is washed with water (200 ml), dried overNa₂SO₄ and concentrated to dryness. In this way, a brown oil is obtainedwhich is then used without further purification.

Stage 17c: 1-(2-thienyl)-cyclohexylamine

Lithium aluminium hydride (2.28 g, 60 mmoles) in 250 ml of THF isintroduced into a 500 ml three-necked flask at 0° C. The azide obtainedin the previous Stage 17b (13.5 g, 65 mmoles) dissolved in 30 ml of THFis introduced dropwise. The reaction medium is agitated for 24 hours atambient temperature. The minimum amount of ammonium hydroxide (10%) isadded very slowly in order to destroy the excess LiAlH₄, followed byfiltration on celite, the precipitate is washed with dichloromethane(300 mnl) and concentrated to dryness. The oil obtained is taken up inether and extracted with an HCl solution (10%) (3×100 ml). The aqueousphase is then neutralised with ammonium hydroxide (20%) and extractedwith ether (3×100 ml). The organic phase is washed with water, driedover MgSO₄ and concentrated to dryness. The product obtained is purifiedby chromatography on alumina eluting with an EP/EA (60/40) mixture. Inthis way, a slightly yellow oil is obtained (8.1 g, 69%).

NMR ¹³C: 156.70 (C2′); 125.99 to 120.85 (C3′ to C5′); 52.82 (C1); 40.39(C2-C6); 25.17 (C4); 22.10 (C3-C5).

Stage 17d: N-acetoxy-1-(2-thienyl)-cyclohexylamine

The amine of Stage 17c (3 g, 16.6 mmoles) in pyridine (100 ml) isintroduced into a 250 ml three-necked flask, and acetic anhydride (51 g,50 mmoles) is added dropwise. After 4 hours under agitation at ambienttemperature, 100 ml of an HCl solution (10%) is added and the productformed is extracted with ether (3×50 ml). The organic phase is washedwith an HCl solution (10%) (2×80 ml), then with water (2×80 ml), driedover MgSO₄ and concentrated to dryness. In this way, a white solid isobtained (3.1 g, 84%).

NMR ¹³C: 169.44 (CO); 152.48 (C2′); 126.32 to 122.68 (C3′ to C5′); 56.69(C1); 37.32 (C2-C6); 25.22 (C4); 24.10 (CH₃); 22.11 (C3-C5).

Stage 17e: N-ethyl-1-(2-thienyl)-cyclohexylamine

Lithium aluminium hydride (0.51 g, 13.4 mmoles) in 80 ml of THF isintroduced into a 500 ml three-necked flask at 0° C. The amine obtainedin the previous Stage 17d (3 g, 13.4 mmoles) dissolved in 30 ml of THFis added dropwise. The reaction medium is agitated for 48 hours underreflux. The minimum amount of ammonium hydroxide (10%) is added veryslowly in order to destroy the excess LiAlH₄, followed by filtering oncelite, the precipitate is washed with dichloromethane (300 ml) andconcentrated to dryness. The oil obtained is taken up in ether andextracted with an HCl solution (10%) (3×100 ml). The aqueous phase isthen neutralised with ammonium hydroxide (20%) and extracted with ether(3×100 ml). The organic phase is washed with water, dried over MgSO₄ andconcentrated to dryness. The product obtained is purified bychromatography on alumina eluting with an EP/EA (90/10) mixture. In thisway, a colourless oil (1.7 g, 61%) is obtained.

NMR ¹³C: 154.18 (C2′); 125.81 to 122.52 (C3′ to C5′); 56.60 (C1); 37.60(CH₂); 35.74 (C2-C6); 25.51 (C4); 21.86 (C3-C5); 15.48 (CH₃).

Characteristics of the corresponding hydrochloride:

M.p.=214-216° C. NMR ¹³C: 139.53 (C2′); 128.49 to 126.65 (C3′ to C5′);62.12 (C1); 36.30 (CH₂); 34.46 (C2-C6); 24.30 (C4); 21.94 (C3-C5); 11.53(CH₃).

Example 18 N-[1-(2-furyl)-cyclohexan-1-yl] piperidine

A solution of MgBr₂ is prepared from 1,2-dibromo-ethane (6.76 g, 36mmol, 4 eq) and magnesium (0.88 g, 36 mmol, 4 eq) in ether (80 ml) undera nitrogen atmosphere. A 2-lithio-furan solution is prepared undernitrogen atmosphere by adding a 1.6M solution of n-butyl-lithium inhexane (28 ml, 45 mmol, 5 eq) dropwise to a mixture of furan (3.1 g, 45mmol, 5 eq) and TMEDA (5.2 g, 45 mmol, 5 eq) in anhydrous ether (100 ml)at −20° C. The mixture is then taken to reflux for 2 hours, cooled downto ambient temperature and MgBr₂ in ether is added dropwise to thesolution. A 1-piperidin-1-yl-cyclohexanecarbonitrile (1.7 g, 9 mmol, 1eq) solution in ether is added dropwise at ambient temperature. Themixture is taken to reflux for 16 hours, cooled down to ambienttemperature, then treated in the following manner: the mixture is pouredgently into an ice-cooled saturated solution of NH₄Cl, agitated for 30minutes, extracted with ether; the ethereal phases are combined, thenextracted three times with 10% HCl, and 20% NH₄OH is added to theaqueous phase until neutrality. The aqueous phase is extracted withether, the organic phase is washed with water, dried over Na₂SO₄,filtered and concentrated under vacuum. The crude product is purified bychromatography on alumina with CH₂Cl₂ as eluent in order to produce anoil (1.7 g, 76%).

NMR ¹³C: 146.46 (C2′); 143.0 (C5′); 113.7 (C3′); 110.7 (C4′); 67.6 (C4);47.0 (Cα); 29.8 (C3-C5); 23.4 (C1); 22.5 (C2-C6); 22.3 (Cβ); 21.7 (Cγ).

The corresponding hydrochloride is obtained in the form of a whitesolid. M.p.=166-167° C.

Example 19 N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl] piperidineExample 20 N-[4-(2-thienyl)-tetrahydro-4H-pyran-4-yl] piperidine Example21 N-[3-(2-thienyl)-tetrahydro-4H-thiopyran-3-yl] piperidine Example 22N-[1-(2-thienyl)-cyclohexan-1-yl]-3-methyl piperidine

The compounds corresponding to Examples 19 and 20 are described in Eur.J. Med. Chem. (1996) 31, pp 488-495. The compounds corresponding toExamples 21 and 22 are described in Arch. Pharm. (1987) vol. 320, no. 4pp 348-361 and Eur. J. Med. Chem. (1995) 30, pp 463-470 respectively.

Using the process described above, the following compounds, which alsoform part of the invention, can also be prepared:

Example X Y Z R4 R₁R₂N— Ar A C S C H

B C S C 5-CH₃ Et₂N—

C C O C H

D S C S H

E C O C H

F S C C H

G C O C H

H C O C H EtMeN—

I C S C 3-CH₃

J C O C H

K C O C H

Pharmacological Study of the Compounds of the Invention

Principle of the affinity measurements in vitro

The affinity of the compounds for their potential bond site, can beevaluated by quantifying their ability to displace a specific tritiatedlabel of a given site. The bond experiences are carried out bycompetition between the molecule to be tested and the appropriateradioligand on a membrane preparation rich in sites to be studied. Theconcentration of the derivative tested which inhibits 50% of the bond ofthe radioligand to the receptor is called IC₅₀.

For the PCP₁ sites, the tritiated label used is [³H]TCP and the testsare carried out on membrane preparations originating from anteriorcerebrum homogenates of rats.

For the experimental conditions and membrane preparation techniquesused, reference can be made to the literature (Brain Res., 378, 133-141(1986); Eur. J. Pharm., 81, 531-542 (1982)).

For low affinity sites, the monosite treatment used led to incoherentresults. The experimental data have therefore been reprocessed usingnon-linear regression (Marquardt-Levenberg algorithm) with Sigma Plotsoftware (Jandel) according to a model with two noted sites ofinteraction PCP₂ and PCP₃. This processing proves to be more suitablethan a monosite treatment (Student test: p<0.05) over a set of 3 to 4experiments for each compound tested. Over all the experiments, the twosite populations are found in a relative proportion to 68.0% (±1.5) forthe PCP₂ sites and 31.2% (±1.5) for the PCP₃ sites.

For the PCP₂ and PCP₃ sites, the preparation originates from ratcerebella. Not having a specific label, only [³H]TCP can be used. A moresignificant concentration of tritiated ligand (2.5 nM versus 1 nM in thecortex) is used to ensure that all the PCP₂ and PCP₃ sites are occupied.The IC₅₀ values are presented in Table 1 below.

Percentage inhibition on PCP receptors:

The tritiated label used is [³H]TCP and the tests are carried out onmembrane preparations originating from cerebral cortex of a rat (BrainRes., 378, 133-141 (1986).

Compound (10 μM) % inhibition Ex 9 96 Ex 10 18

TABLE 1 cortex cerebellum 1 site 2 sites IC₅₀ IC₅₀ PCP₂ IC₅₀ PCP₃Compound (nM) nH n (nM) (%) (nM) (%) n TCP — — — 59 72.6 3716 29.8 5 Ex1 17233 0.94 3 — — — — — (majority) Ex 1 26.8 0.89 3 1355 62.8 17.6 34.74 (minority) Ex 2 132 1.14 3 265 69.1 2850 31.6 3 Ex 4 24 0.84 3 53.266.3 2076 34.6 4 Ex 5 >100 μM — 3 >100 μM 66.2 581 32.2 3 Ex 6 >100 μM —3 >100 μM 55.6 280 39.4 3 Ex 7 82825 0.73 4 84000 57.8 639 40.7 3 Ex 828.4 0.96 3 2240 69 12.4 31 3 Ex 9 133 0.87 3 1015 68.3 13.8 32.3 5 Ex10 27467 0.9 3 26633 65.0 59.1 33.4 3 Ex 11 462 0.97 3 532 83 >100 μM15.3 3 Ex 12 77.8 0.93 3 772 76.4 5.4 21.8 4 Ex 17 20.9 0.77 3 55 56.647600 44.6 3 Ex 18 7.8 0.83 3 187 66.3 5.6 30.7 3 Ex 19 71.6 1.05 3 58675.2 8.5 25.2 3 Ex 20 1223 0.98 3 5840 80.3 35 15.5 3 Ex 21 73.4 1.00 3659 77.8 8.0 23.4 3 Ex 22 (±) 5.5 1.09 3 47.3 68.5 1450 33.7 3 (+) 5.21.04 28.3 52.5 808 51.0 (−) 158 1.08 — — — —

What is claimed is:
 1. A compound selected from the group consisting ofall racemic, enantiomeric ad diastereoisomeric forms of a compound ofthe formula

wherein Ar is selected from the group consisting of monocyclic,carbocyclic and heterocyclic aryl of 5 to 6 ring members or of condensedrings unsubstituted or substituted with at least one member of the groupconsisting of a) alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyland hydroxyalkyl of up to 6 carbon atoms and b) halogen, —OH, —CN, —NO₂,—NH₂ mono and dialkylamino of 1 to 6 alkyl carbon atoms, carboxy,salified carboxy and carboxy esterified with an alkanol of 1 to 6 carbonatoms, R₁ and R₂ are individually hydrogen or alkyl of up to 6 carbonatoms unsubstituted or substituted with at least one member of the groupconsisting of —OH, —CN, —NO₂, carboxy, salified carboxy and carboxyesterified with an alkanol of 1 to 6 carbon atoms or R₁ and R₂ togetherwith the nitrogen to which they are attached form

n is an integer from 0 to 2, R₃, R′₃ and R₄ are individually selectedfrom the group consisting of a) hydrogen, halogen, —OH, —CN, —NO₂,carboxy, salified carboxy, carboxy esterified with an alkanol of 1 to 6carbon atoms and b) alkyl, alkenyl, alkynyl, alkoxy, alkylthio,haloalkyl and hydroxyalkyl of up to 6 carbon atoms, and one of X, Y andZ is sulfur or oxygen and the other two are methylene with the exceptionof the compounds when R₃, R′₃ and R₄ are all hydrogen, 1) Ar is phenylor 2-thienyl, R₁ and R₂ with the nitrogen form pyrrolidino and one of X,Y and Z is oxygen, or 2) R₁ and R₂ with the nitrogen form piperidino, Aris phenyl, thienyl or benzothienyl, Y is sulfur and X and Z aremethylene, 3) R₁ and R with the nitrogen form piperidino, Y is oxygen, Xand Z are methylene and Ar is selected from the group consisting ofphenyl, methoxyphenyl, benzothienyl and 2-thienyl, 4) R₁ and R₂ with thenitrogen form piperidino, Ar is phenyl, methoxyphenyl or 2-thienyl, oneof X or Z is oxygen and the other and Y are methylene, 5) R₁ and R₂ withthe nitrogen form piperidino, Ar is phenyl or 2-thienyl, one of X and Zis sulfur and the other and Y are methylene, 6) R₁ and R₂ with nitrogenform pyrrolidino, Ar is 2-thienyl, one of X or Z is sulfur and the otherand Y are methylene, 7) R₁ and R₂ with the nitrogen form ethylamino orpyrrolidino, Ar is phenyl, Y is sulfur and X and Z are methylene or 8)—N-[1-(2-thienyl)-cyclohexan-1-yl]-3-hydroxymethyl-piperidine,—N-[1-(2-thienyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidine,—N-[1-(2-benzothiophenyl)-cyclohexan-1-yl]-4-hydroxy-3-methylpiperidine, —N-[1-(2-thienyl)-cyclohexan-1-yl]-3-methyl-piperidine,—N-ethyl-1-(2-thienyl)-cyclohexylamine, or—N-[1-(2-furyl)-cyclohexan-1-yl] piperidine, and their non-toxic,pharmaceutically acceptable salts with bases and acids.
 2. A compound ofclaim 1 wherein R₁ and R₂ are individually hydrogen or alkyl of 1 to 6carbon atoms or together with the nitrogen form

and R₃ and R′₃ are individually selected from the group consisting ofhydrogen, —OH and alkyl and hydroxyalkyl of 1 to 6 carbon atoms and Aris an heterocyclic aryl, monocyclic with 5 members or constituted by twocondensed rings and unsubstituted or substituted by at least one alkylor alkylene.
 3. A compound of claim 1 wherein Ar is selected from thegroup consisting of thienyl, furyl, benzothienyl and benzofuryl, allunsubstituted or substituted with at least one member of the groupconsisting of methyl, ethyl, propyl and alkyl, R₁ and R₂ areindividually hydrogen or methyl or ethyl or with the nitrogen atom form

wherein R₃ and R′₃ are individually selected from the group consistingof hydrogen, —OH, hydroxymethyl, methyl, ethyl and hydroxyethyl.
 4. Asmedicaments, the compounds of formula I as defined in claim 1, as wellas the addition salts with mineral or organic acids or pharmaceuticallyacceptable mineral or organic bases of said compounds of formula I. 5.As medicaments, the compounds of formula I_(A) as defined in claim 2, aswell as the addition salts with pharmaceutically acceptable mineral ororganic acids or mineral or organic bases of said compounds of formulaI_(A).
 6. Pharmaceutical compositions containing, as active ingredient,at least one of the medicaments as defined in claim
 5. 7. A method ofprotecting central or peripheral nervous system cells against acutedegeneration induced by accidents in warm-blooded animals comprisingadministering to warm-blooded animals an amount of a compound of theformula

wherein Ar′ is monocyclic carbocyclic or heterocyclic aryl of 5 to 6ring members or condensed rings, each unsubstituted or substituted withat least one member of the group consisting of a) halogen, —OH andalkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl and hydroxy alkylof up to 6 carbon atoms, b) carboxy, salified carboxy and carboxyesterified with an alkanol of up to 6 carbon atoms and c) —CN, —NO₂,—NH₂ and mono and dialkylamino of 1 to 6 alkyl carbon atoms, R′₁ and R′₂are individually hydrogen or alkyl of 1 to 6 carbon atoms unsubstitutedor substituted with at least one member of the group consisting of —OH,—CN, —NO₂, carboxy, salified carboxy and carboxy esterified with analkanol of up to 6 carbon atoms or R′₁ and R′₂ taken with the nitrogento which they are attached are:

n is an integer from 0 to 2, R₃ and R′₃ are individually selected fromthe group consisting of a) hydrogen, halogen, —OH, —CN, —NO₂, carboxy,salified carboxy, carboxy esterified with an alkanol of up to 6 carbonatoms and b) alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl andhydroxyalkyl of up to 6 carbon atoms, R′₄ has the definition of R₃ orR′₃, one of X′, Y′ and Z′ is oxygen or sulfur and the other two aremethylene or all are methylene or a compound selected from the group—N-[1-(2-thienyl)-cyclohexan-1-yl]-3-hydroxymethyl-piperidine,—N-[1-(2-thienyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidine,—N-[1-(2-benzothiophenyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidineor —N-ethyl-1-(2-thienyl)-cyclohexylamine,—N-[1-(2-furyl-cyclohexan-1-yl] piperidine,—N-[1-(2-thienyl)-cyclohexan-1-yl]-3-methyl-piperidine, in all possibleracemic, enantiomeric and diastereolsomeric forms and its non-toxic,pharmaceutically acceptable addition salts sufficient to protect centraland peripheral nervous system cells against acute degeneration caused byaccidents.
 8. The method of claim 7 wherein the compound is of formulaI′_(A) wherein Ar′ represents an heterocyclic aryl radical, monocyclicwith 5 members or constituted by two condensed rings and optionallysubstituted by one or more identical or different alkyl or alkenylradicals; R′₁ and R′₂, identical or different, represent a hydrogen atomor an alkyl radical having at most 6 carbon atoms or R₁ and R₂ form withthe nitrogen atom to which they are linked a

 radical in which n is equal to 1 and R₃ and R′₃, identical ordifferent, represent a hydrogen atom or a hydroxyl, alkyl orhydroxyalkyl radical having at most 6 carbon atoms.
 9. The method ofclaim 7 wherein the compound is of formula I′_(A) wherein Ar′ representsthe thienyl, furyl, benzothienyl, benzofuryl radical and optionallysubstituted by one or more methyl, ethyl, propyl or allyl radicals; R′₁and R′₂ identical or different represent a hydrogen atom or a methyl orethyl radical, or R₁ and R₂ form with the nitrogen atom to which theyare linked a

 radical in which n is equal to 1 and R₃ and R′₃, identical ordifferent, represent a hydrogen atom or a hydroxyl, hydroxymethyl,hydroxyethyl, methyl or ethyl radical, for the preparation ofmedicaments as defined above.
 10. The method of claim 7 wherein thecompound is selected from the group consisting of:—N-[4-(2-thienyl)-3-methyl-tetrahydro-4H-thiopyran4-yl]-piperidine;—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran4-yl]-3-methyl-piperidine;—N-[4-(2-benzothiophenyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine;—N-[4-(2-furyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;—N-[4-(2-benzofuranyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;—N-[4-(5-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;—N-[4-(4-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-hydroxy piperidine;—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-4-hydroxy piperidine.11. A method of protecting central or peripheral nervous system cellsagainst chronic degeneration induced by neurodegenerative diseases inwarm-blooded animals comprising administering to warm-blooded animals anamount of a compound of the formula

wherein Ar′ is monocyclic carbocyclic or heterocyclic aryl of 5 to 6ring members or condensed rings, each unsubstituted or substituted withat least one member of the group consisting of a) halogen, —OH andalkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl and hydroxy alkylof up to 6 carbon atoms, b) carboxy, salified carboxy and carboxyesterified with an alkanol of up to 6 carbon atoms and c) —CN, —NO₂,—NH₂ and mono and dialkylamino of 1 to 6 alkyl carbon atoms, R′₁ and R′₂are individually hydrogen or alkyl of 1 to 6 carbon atoms unsubstitutedor substituted with at least one member of the group consisting of —OH,—CN, —NO₂, carboxy, salified carboxy and carboxy esterified with analkanol of up to 6 carbon atoms or R′₁ and R′₂ taken with the nitrogento which they are attached are:

n is an integer from 0 to 2, R₃ and R′₃ are individually selected fromthe group consisting of a) hydrogen, halogen, —OH, —CN, —NO₂, carboxy,salified carboxy, carboxy esterified with an alkanol of up to 6 carbonatoms and b) alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl andhydroxyalkyl of up to 6 carbon atoms, R′₄ has the definition of R₃ orR′₃, one of X′, Y′ and Z′ is oxygen or sulfur and the other two aremethylene or all are methylene or a compound selected from the group—N-[1-(2-thienyl)-cyclohexan-1-yl]-3-hydroxymethyl-piperidine,—N-[1-(2-thienyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidine,—N-[1-(2-benzothiophenyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidineor —N-ethyl-1-(2-thienyl)-cyclohexylamine,—N-[1-(2-furyl)-cyclohexan-1-yl] piperidine,—N-[1-(2-thienyl)-cyclohexan-1-yl]-3-methyl-piperidine, in all possibleracemic, enantiomeric and diastereoisomeric forms and its non-toxic,pharmaceutically acceptable addition salts sufficient to protect thecentral and peripheral nervous system cells against chronic degenerationinduced by neurodegenerative diseases.
 12. A method of treating a stateof dependency on addictive drugs in warm-blooded animals comprisingadministering to warm-blooded animals an amount of a compound theformula

wherein Ar′ is monocyclic carbocyclic or heterocyclic aryl of 5 to 6ring members or condensed rings, each unsubstituted or substituted withat least one member of the group consisting of a) halogen, —OH andalkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl and hydroxy alkylof up to 6 carbon atoms, b) carboxy, salified carboxy and carboxyesterified with an alkanol of up to 6 carbon atoms and c) —CN, —NO₂,—NH₂ and mono and dialkylamino of 1 to 6 alkyl carbon atoms, R′₁ and R′₂are individually hydrogen or alkyl of 1 to 6 carbon atoms unsubstitutedor substituted with at least one member of the group consisting of —OH,—CN, —NO₂, carboxy, salified carboxy and carboxy esterified with analkanol of up to 6 carbon atoms or R′₁ and R′₂ taken with the nitrogento which they are attached are:

n is an integer from 0 to 2, R₃ and R′₃ are individually selected fromthe group consisting of a) hydrogen, halogen, —OH, —CN, —NO₂, carboxy,salified carboxy, carboxy esterified with an alkanol of up to 6 carbonatoms and b) alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl andhydroxyalkyl of up to 6 carbon atoms, R′₄ has the definition of R₃ orR′₃, one of X′, Y′ and Z′ is oxygen or sulfur and the other two aremethylene or all are methylene or a compound selected from the group—N-[1-(2-thienyl)-cyclohexan-1-yl]-3-hydroxymethyl-piperidine,—N-[1-(2-thienyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidine,—N-[1-(2-benzothiophenyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidineor —N-ethyl-1-(2-thienyl)-cyclohexylamine,—N-[1-(2-furyl)-cyclohexan-1-yl] piperidine,—N-[1-(2-thienyl)-cyclohexan-1-yl]-3-methyl-piperidine, in all possibleracemic, enantiomeric and diastereoisomeric forms and its non-toxic,pharmaceutically acceptable addition salts sufficient to treatdependency on addictive drugs.
 13. Preparation process for the compoundsof general formula I as defined in claim 1, characterized in that itcomprises the reaction of a compound of formula 1

 in which X″, Y″, Z″ represent a sulphur or oxygen atom or a methyleneradical, R₄ has the meaning indicated above, with a aryl magnesiumhalide of formula Ar—Mg—Hal in which Hal represents a halogen atom andAr has the meaning indicated above, in order to obtain the compound offormula 2

in which X″, Y″, Z″, Ar and R₄ have the meanings indicated above, theconversion of the hydroxyl radical of the alcohol of formula 2 thusobtained, to the azide of formula 3

in which X″, Y″, Z″, Ar and R₄ have the meaning indicated above, thenthe reduction of the azide of formula 3 to the primary amine of formula4

in which X″, Y″, Z″, Ar and R₄ have the meanings given above; andfinally, if the desired compound of formula I is such that at least oneof the R₁ or R₂ radicals is different from the hydrogen atom or R₁ andR₂ form a ring with the nitrogen atom to which they are linked, thetreatment of this compound of formula 4 in order to obtain the compoundof formula I which is converted into the salt if desired.
 14. A processfor the preparation of a compound of claim 1 comprising reacting acompound of formula I

in which X″, Y″, Z″ and R₄ have the meaning of claim 1 in anhydrousmedium, with a compound of the formula R₁R₂NH in which R₁ and R₂ havethe meanings of claim 1 and a cyanide ion donor compound to obtain thecompound of formula 5

in which X″, Y″, Z″ and R₁ and R₂ have the meanings indicated above andreacting the compound of formula 5 with an aryl magnesium halide of theformula Ar—Mg—Hal in which Ar has the meaning of claim 1 and Hal ishalogen to obtain the compound of formula I.
 15. A compound of claim 1selected from the group consisting of:—N-[4-(2-thienyl)-3-methyl-tetrahydro-4H-thiopyran-4-yl]-piperidine;—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine;—N-[4-(2-benzothiophenyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine;—N-[4-(2-furyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;—N-[4-(2-benzofuranyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;—N-[4-(5-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;—N-[4-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-hydroxy piperidine or—N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-4-hydroxy piperidine.